scholarly journals The impact of D-cycloserine and sarcosine on in vivo frontal neural activity in a schizophrenia-like model

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Lulu Yao ◽  
Zongliang Wang ◽  
Di Deng ◽  
Rongzhen Yan ◽  
Jun Ju ◽  
...  
Keyword(s):  
Neural Activity ◽  
Brain Activity ◽  
Brain Slices ◽  
Unit Recording ◽  
Glycine Transporter 1 ◽  
Glycine Transporter ◽  
Neural Spiking ◽  
In Vivo Calcium Imaging ◽  
The Impact

Abstract Background N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo. Methods By using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice. Results In vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice. Conclusions We conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.

scholarly journals Multi-shanks SiNAPS Active Pixel Sensor CMOS probe: 1024 simultaneously recording channels for high-density intracortical brain mapping

2019 ◽  
Author(s):  
Fabio Boi ◽  
Nikolas Perentos ◽  
Aziliz Lecomte ◽  
Gerrit Schwesig ◽  
Stefano Zordan ◽  
...  
Keyword(s):  
Neural Activity ◽  
Brain Activity ◽  
Brain Area ◽  
Large Population ◽  
Brain Structures ◽  
High Density ◽  
Single Neurons ◽  
Electrode Arrays ◽  
Unit Recording ◽  
Recording Channels

AbstractThe advent of implantable active dense CMOS neural probes opened a new era for electrophysiology in neuroscience. These single shank electrode arrays, and the emerging tailored analysis tools, provide for the first time to neuroscientists the neurotechnology means to spatiotemporally resolve the activity of hundreds of different single-neurons in multiple vertically aligned brain structures. However, while these unprecedented experimental capabilities to study columnar brain properties are a big leap forward in neuroscience, there is the need to spatially distribute electrodes also horizontally. Closely spacing and consistently placing in well-defined geometrical arrangement multiple isolated single-shank probes is methodologically and economically impractical. Here, we present the first high-density CMOS neural probe with multiple shanks integrating thousand’s of closely spaced and simultaneously recording microelectrodes to map neural activity across 2D lattice. Taking advantage from the high-modularity of our electrode-pixels-based SiNAPS technology, we realized a four shanks active dense probe with 256 electrode-pixels/shank and a pitch of 28 µm, for a total of 1024 simultaneously recording channels. The achieved performances allow for full-band, whole-array read-outs at 25 kHz/channel, show a measured input referred noise in the action potential band (300-7000 Hz) of 6.5 ± 2.1µVRMS, and a power consumption <6 µW/electrode-pixel. Preliminary recordings in awake behaving mice demonstrated the capability of multi-shanks SiNAPS probes to simultaneously record neural activity (both LFPs and spikes) from a brain area >6 mm2, spanning cortical, hippocampal and thalamic regions. High-density 2D array enables combining large population unit recording across distributed networks with precise intra- and interlaminar/nuclear mapping of the oscillatory dynamics. These results pave the way to a new generation of high-density and extremely compact multi-shanks CMOS-probes with tunable layouts for electrophysiological mapping of brain activity at the single-neurons resolution.

Activation of a Classic Hunger Circuit Slows Luteinizing Hormone Pulsatility

2019 ◽  
Vol 110 (7-8) ◽  
pp. 671-687 ◽  
Author(s):  
Eulalia A. Coutinho ◽  
Melanie Prescott ◽  
Sabine Hessler ◽  
Christopher J. Marshall ◽  
Allan E. Herbison ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Ex Vivo ◽  
Polycystic Ovary ◽  
Brain Slices ◽  
Pulse Frequency ◽  
Pulse Generation ◽  
Electrophysiological Studies ◽  
The Impact ◽  
Lh Secretion

Introduction: The central regulation of fertility is carefully coordinated with energy homeostasis, and infertility is frequently the outcome of energy imbalance. Neurons in the hypothalamus expressing neuropeptide Y and agouti-related peptide (NPY/AgRP neurons) are strongly implicated in linking metabolic cues with fertility regulation. Objective: We aimed here to determine the impact of selectively activating NPY/AgRP neurons, critical regulators of metabolism, on the activity of luteinizing hormone (LH) pulse generation. Methods: We employed a suite of in vivo optogenetic and chemogenetic approaches with serial measurements of LH to determine the impact of selectively activating NPY/AgRP neurons on dynamic LH secretion. In addition, electrophysiological studies in ex vivo brain slices were employed to ascertain the functional impact of activating NPY/AgRP neurons on gonadotropin-releasing hormone (GnRH) neurons. Results: Selective activation of NPY/AgRP neurons significantly decreased post-castration LH secretion. This was observed in males and females, as well as in prenatally androgenized females that recapitulate the persistently elevated LH pulse frequency characteristic of polycystic ovary syndrome (PCOS). Reduced LH pulse frequency was also observed when optogenetic stimulation was restricted to NPY/AgRP fiber projections surrounding GnRH neuron cell bodies in the rostral preoptic area. However, electrophysiological studies in ex vivo brain slices indicated these effects were likely to be indirect. Conclusions: These data demonstrate the ability of NPY/AgRP neuronal signaling to modulate and, specifically, reduce GnRH/LH pulse generation. The findings suggest a mechanism by which increased activity of this hunger circuit, in response to negative energy balance, mediates impaired fertility in otherwise reproductively fit states, and highlight a potential mechanism to slow LH pulsatility in female infertility disorders, such as PCOS, that are associated with hyperactive LH secretion.

scholarly journals Chromosomal Proteins HMGN3a and HMGN3b Regulate the Expression of Glycine Transporter 1

2004 ◽  
Vol 24 (9) ◽  
pp. 3747-3756 ◽  
Author(s):  
Katherine L. West ◽  
Meryl A. Castellini ◽  
Melinda K. Duncan ◽  
Michael Bustin
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Transcriptional Start Site ◽  
Ectopic Expression ◽  
Gene Expression Profiles ◽  
Specific Gene ◽  
Glycine Transporter 1 ◽  
Glycine Transporter ◽  
Synaptic Junctions

ABSTRACT HMGN proteins promote chromatin unfolding, enhance access to nucleosomes, and modulate transcription from chromatin templates. It is not known whether they act indiscriminately as general modulators of transcription or whether they regulate specific gene expression. Here, we investigated the role of HMGN3, a recently discovered HMGN family member, in transcription in vivo. We created cell lines overexpressing HMGN3a or its splice variant, HMGN3b, and analyzed their gene expression profiles using microarrays and reverse transcriptase PCR. We found that ectopic expression of HMGN3a alters the expression of approximately 0.8% of genes. Both HMGN3a and HMGN3b upregulate the expression of the glycine transporter 1 gene (Glyt1). Glyt1 encodes a membrane transporter that regulates the glycine concentration in synaptic junctions. Both GLYT1 and HMGN3 are highly expressed in glia cells and the eye, and we show that both proteins are coexpressed in the retina. Chromatin immunoprecipitation assays showed that HMGN3 protein is recruited to a region of the Glyt1 gene encompassing the Glyt1a transcriptional start site. These results suggest that HMGN3 regulates Glyt1 expression and demonstrate that members of the HMGN family can regulate the transcription of specific genes.

A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies

2008 ◽  
Vol 35 (3) ◽  
pp. 315-325 ◽  
Author(s):  
Zhizhen Zeng ◽  
Julie A. O'Brien ◽  
Wei Lemaire ◽  
Stacey S. O'Malley ◽  
Patricia J. Miller ◽  
...  
Keyword(s):  
Glycine Transporter 1 ◽  
Glycine Transporter

In vivo evaluation of carbon-11-labelled non-sarcosine-based glycine transporter 1 inhibitors in mice and conscious monkeys

2011 ◽  
Vol 38 (4) ◽  
pp. 517-527 ◽  
Author(s):  
Jun Toyohara ◽  
Kiichi Ishiwata ◽  
Muneyuki Sakata ◽  
Jin Wu ◽  
Shingo Nishiyama ◽  
...  
Keyword(s):  
In Vivo Evaluation ◽  
Glycine Transporter 1 ◽  
Glycine Transporter

scholarly journals Image-guided neural activity manipulation with a paramagnetic drug

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sarah Bricault ◽  
Ali Barandov ◽  
Peter Harvey ◽  
Elizabeth DeTienne ◽  
Aviad Hai ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Neural Activity ◽  
Brain Activity ◽  
Pharmacological Properties ◽  
Resonance Imaging ◽  
Significant Challenge ◽  
Image Guided

AbstractTargeted manipulations of neural activity are essential approaches in neuroscience and neurology, but monitoring such procedures in the living brain remains a significant challenge. Here we introduce a paramagnetic analog of the drug muscimol that enables targeted neural inactivation to be performed with feedback from magnetic resonance imaging. We validate pharmacological properties of the compound in vitro, and show that its distribution in vivo reliably predicts perturbations to brain activity.

scholarly journals Measurement of Bmax and Kd with the Glycine Transporter 1 Radiotracer 18F-MK6577 using a Novel Multi-Infusion Paradigm

2015 ◽  
Vol 35 (12) ◽  
pp. 2001-2009 ◽  
Author(s):  
Yan Xia ◽  
Ming-Qiang Zheng ◽  
Daniel Holden ◽  
Shu-fei Lin ◽  
Michael Kapinos ◽  
...  
Keyword(s):  
Rank Order ◽  
Target Concentration ◽  
Glycine Transporter 1 ◽  
Glycine Transporter ◽  
Positron Emission ◽  
Fitting Method ◽  
The Brain

Glycine is a co-agonist of glutamate at the NMDA receptor. Glycine transporter 1 (GlyT1) inhibitors are reported to be potential therapeutic agents for schizophrenia. 18F-MK6577 is a new positron emission tomography (PET) radiotracer useful for imaging brain GlyT1 and its occupancy in humans. We devised a novel multi-infusion paradigm of radiolabeled and unlabeled compound and an iterative linear/nonlinear alternating fitting method to allow for the determination of in vivo affinity ( Kd) and target concentration ( Bmax) images, constraining Kd to be uniform across the brain. This paradigm was tested with 18F-MK6577 in baboons. Voxel-based analysis produced high quality Bmax images and reliable Kd estimates, and also suggested that the nondisplaceable distribution volume ( VND) is not uniform throughout the brain. In vivo GlyT1 Kd was estimated to be 1.87 nmol/L for 18F-MK6577, and the rank order of GlyT1 distribution measured in the baboon brain was: high in the brainstem (133 nmol/L), medium in the cerebellum (83 nmol/L), and low in the cortex (30 nmol/L). These in vivo Kd and Bmax values agreed well with those determined in vitro, thus validating our novel multi-infusion approach.

scholarly journals Sparse but Selective and Potent Synaptic Transmission From the Globus Pallidus to the Subthalamic Nucleus

2009 ◽  
Vol 102 (1) ◽  
pp. 532-545 ◽  
Author(s):  
Jérôme Baufreton ◽  
Erin Kirkham ◽  
Jeremy F. Atherton ◽  
Ariane Menard ◽  
Peter J. Magill ◽  
...  
Keyword(s):  
Globus Pallidus ◽  
Subthalamic Nucleus ◽  
Brain Slices ◽  
Synaptic Connections ◽  
Electron Microscopic ◽  
Autonomous Activity ◽  
The Impact ◽  
Stimulation Technique ◽  
Minimal Stimulation

The reciprocally connected GABAergic globus pallidus (GP)-glutamatergic subthalamic nucleus (STN) network is critical for voluntary movement and an important site of dysfunction in movement disorders such as Parkinson's disease. Although the GP is a key determinant of STN activity, correlated GP-STN activity is rare under normal conditions. Here we define fundamental features of the GP-STN connection that contribute to poorly correlated GP-STN activity. Juxtacellular labeling of single GP neurons in vivo and stereological estimation of the total number of GABAergic GP-STN synapses suggest that the GP-STN connection is surprisingly sparse: single GP neurons maximally contact only 2% of STN neurons and single STN neurons maximally receive input from 2% of GP neurons. However, GP-STN connectivity may be considerably more selective than even these estimates imply. Light and electron microscopic analyses revealed that single GP axons give rise to sparsely distributed terminal clusters, many of which correspond to multiple synapses with individual STN neurons. Application of the minimal stimulation technique in brain slices confirmed that STN neurons receive multisynaptic unitary inputs and that these inputs largely arise from different sets of GABAergic axons. Finally, the dynamic-clamp technique was applied to quantify the impact of GP-STN inputs on STN activity. Small fractions of GP-STN input were sufficiently powerful to inhibit and synchronize the autonomous activity of STN neurons. Together these data are consistent with the conclusion that the rarity of correlated GP-STN activity in vivo is due to the sparsity and selectivity, rather than the potency, of GP-STN synaptic connections.

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